ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes.

BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.

A 4D-Printable Photocurable Resin Derived from Waste Cooking Oil with Enhanced Tensile Strength.

In pursuit of enhancing the mechanical properties, especially the tensile strength, of 4D-printable consumables derived from waste cooking oil (WCO), we initiated the production of acrylate-modified WCO, which encompasses epoxy waste oil methacrylate (EWOMA) and epoxy waste oil acrylate (EWOA). Subsequently, a series of WCO-based 4D-printable photocurable resins were obtained by introducing a suitable diacrylate molecule as the second monomer, coupled with a composite photoinitiator system comprising Irgacure 819 and p-dimethylaminobenzaldehyde (DMAB). These materials were amenable to molding using an LCD light-curing 3D printer. Our findings underscored the pivotal role of triethylene glycol dimethacrylate (TEGDMA) among the array of diacrylate molecules in enhancing the mechanical properties of WCO-based 4D-printable resins. Notably, the 4D-printable material, composed of EWOA and TEGDMA in an equal mass ratio, exhibited nice mechanical strength comparable to that of mainstream petroleum-based 4D-printable materials, boasting a tensile strength of 9.17 MPa and an elongation at break of 15.39%. These figures significantly outperformed the mechanical characteristics of pure EWOA or TEGDMA resins. Furthermore, the EWOA-TEGDMA resin demonstrated impressive thermally induced shape memory performance, enabling deformation and recovery at room temperature and retaining its shape at -60 °C. This resin also demonstrated favorable biodegradability, with an 8.34% weight loss after 45 days of soil degradation. As a result, this 4D-printable photocurable resin derived from WCO holds immense potential for the creation of a wide spectrum of high-performance intelligent devices, brackets, mold, folding structures, and personalized products.

Iterative Synthesis of 2-Deoxyoligosaccharides Enabled by Stereoselective Visible-Light-Promoted Glycosylation.

The photoinitiated intramolecular hydroetherification of alkenols has been used to form C-O bonds, but the intermolecular hydroetherification of alkenes with alcohols remains an unsolved challenge. We herein report the visible-light-promoted 2-deoxyglycosylation of alcohols with glycals. The glycosylation reaction was completed within 2 min in a high quantum yield (ϕ=28.6). This method was suitable for a wide array of substrates and displayed good reaction yields and excellent stereoselectivity. The value of this protocol was further demonstrated by the iterative synthesis of 2-deoxyglycans with α-2-deoxyglycosidic linkages up to a 20-mer in length and digoxin with ß-2-deoxyglycosidic linkages. Mechanistic studies indicated that this reaction involved a glycosyl radical cation intermediate and a photoinitiated chain process.

Development of a Micro/Nano Probing System Using Double Elastic Mechanisms.

To meet the requirement of high precision measurement of coordinate measurement machine system, a compact microprobe has been designed for 3D measurement in this paper. Aiming to reduce the influences of signal coupling during the probing process, the probe has been designed by adopting two elastic mechanisms, in which the horizontal and vertical motions of the probe tip can be separated by differential signals of quadrant photodetectors in each elastic mechanism. A connecting rod has been designed to transfer the displacement of the probe tip in vertical direction from lower to upper elastic mechanisms. The sensitivity models in horizontal and vertical directions have been established, and the sensor sensitivity has been verified through experiments. Furthermore, the signal coupling of three axes has been analyzed, and mathematical models have been proposed for decoupling. The probing performance has been verified experimentally.

Autonomous enzymatic synthesis of functional nucleic acids for sensitive measurement of long noncoding RNA in human lung tissues.

Aberrant long noncoding RNA (lncRNA) expression is linked to varied pathological processes and malignant tumors, and lncRNA can serve as potential disease biomarkers. Herein, we demonstrate the autonomous enzymatic synthesis of functional nucleic acids for sensitive measurement of lncRNA in human lung tissues on the basis of multiple primer generation-mediated rolling circle amplification (mPG-RCA). This assay involves two padlock probes that act as both a detection probe for recognizing target lncRNA and a domain for producing complementary DNAzyme. Two padlock probes can hybridize with target lncRNA at different sites, followed by ligation to form a circular template with the aid of RNA ligase. The circular template can initiate mPG-RCA to generate abundant Mg2+-dependent DNAzymes that can specifically cleave signal probes to induce the recovery of Cy3 fluorescence. The inherent characteristics of ligase-based ligation reaction and DNAzymes endow this assay with excellent specificity, and the introduction of multiple padlock probes endows this assay with high sensitivity. This strategy can rapidly and sensitively measure lncRNA with a wide linear range of 1 fM - 1 nM and a detection limit of 678 aM within 1.5 h, and it shows distinct advantages of simplicity and immobilization-free without the need of precise temperature control and tedious procedures of nanomaterial preparation. Moreover, it enables accurate measurement of lncRNA level in normal cells and malignant tumor cells as well as differentiation of lncRNA expressions in tissues of non-small cell lung cancer (NSCLC) patients and normal individuals, with promising applications in biomedical studies and disease diagnosis.

Photosensitizer-free visible-light-promoted glycosylation enabled by 2-glycosyloxy tropone donors.

Photochemical glycosylation has attracted considerable attention in carbohydrate chemistry. However, to the best of our knowledge, visible-light-promoted glycosylation via photoactive glycosyl donor has not been reported. In the study, we report a photosensitizer-free visible-light-mediated glycosylation approach using a photoactive 2-glycosyloxy tropone as the donor. This glycosylation reaction proceeds at ambient temperature to give a wide range of O-glycosides or oligosaccharides with yields up to 99%. This method is further applied in the stereoselective preparation of various functional glycosyl phosphates/phosphosaccharides, the construction of N-glycosides/nucleosides, and the late-stage glycosylation of natural products or pharmaceuticals on gram scales, and the iterative synthesis of hexasaccharide. The protocol features uncomplicated conditions, operational simplicity, wide substrate scope (58 examples), excellent compatibility with functional groups, scalability of products (7 examples), and high yields. It provides an efficient glycosylation method for accessing O/N-glycosides and glycans.

A real-world case-control study on the efficacy and safety of pulsed field ablation for atrial fibrillation.

OBJECTIVE: The primary objective of this study was to evaluate the efficacy and safety of pulsed field ablation in individuals diagnosed with atrial fibrillation. METHODS: A total of 36 patients diagnosed with atrial fibrillation were enrolled in the pulsed field ablation group, while another 36 patients diagnosed with atrial fibrillation were included in the radiofrequency ablation group. Among the study participants, 15 patients in the pulsed field ablation group and 17 patients in the radiofrequency ablation group had persistent atrial fibrillation. Comprehensive comparisons were made between the two groups, including baseline data, underlying diseases, medication usage, intraoperative parameters, and atrial fibrillation recurrence rates at 1, 3, and 6 months during the postoperative follow-up period. RESULTS: (1) There were no significant differences observed between the two groups concerning baseline data and antiarrhythmic drug usage (P > 0.05); (2) the effective ablation time for both left and right pulmonary veins in the pulsed field ablation group was markedly shorter compared to the radiofrequency ablation group (P < 0.001 for each vein); (3) within the pulsed field ablation group, the number of discharges, catheter operation time, and effective ablation time for the left pulmonary vein were significantly higher than those for the right pulmonary vein (P < 0.05). Conversely, in the radiofrequency ablation group, the number of discharges for the left pulmonary vein was significantly higher than that for the right pulmonary vein (P < 0.05); and (4) when comparing sinus rhythm maintenance at 1, 3, and 6 months postoperatively, no statistically significant differences were noted between the two groups for paroxysmal, persistent, and paroxysmal + persistent atrial fibrillation cases (P > 0.05). CONCLUSION: During the 6-month follow-up period, pulsed field ablation demonstrated comparable efficacy to radiofrequency ablation with respect to recurrence rates for both paroxysmal and persistent atrial fibrillation. Moreover, pulsed field ablation exhibited high safety levels, excellent surgical efficiency, and a notably brief learning curve, affirming its viability as a therapeutic option for these conditions.

Self-Assembled Core-Shell Nanoscale Coordination Polymer Nanoparticles Carrying a Sialyltransferase Inhibitor for Cancer Metastasis Inhibition.

Despite hypersialylation of cancer cells together with a significant upregulation of sialyltransferase (ST) activity contributes to the metastatic cascade at multiple levels, there are few dedicated tools to interfere with their expression. Although transition state-based ST inhibitors are well-established, they are not membrane permeable. To tackle this problem, herein, we design and construct long-circulating, self-assembled core-shell nanoscale coordination polymer (NCP) nanoparticles carrying a transition state-based ST inhibitor, which make the inhibitor transmembrane and potently strip diverse sialoglycans from various cancer cells. In the experimental lung metastasis and metastasis prevention models, the nanoparticle device (NCP/STI) significantly inhibits metastases formation without systemic toxicity. This strategy enables ST inhibitors to be applied to cells and animals by providing them with a well-designed nanodelivery system. Our work opens a new avenue to the development of transition state-based ST inhibitors and demonstrates that NCP/STI holds great promise in achieving metastases inhibition for multiple cancers.

SZT2 variants associated with partial epilepsy or epileptic encephalopathy and the genotype-phenotype correlation.

Background: Recessive SZT2 variants are reported to be associated with developmental and epileptic encephalopathy 18 (DEE-18) and occasionally neurodevelopment abnormalities (NDD) without seizures. This study aims to explore the phenotypic spectrum of SZT2 and the genotype-phenotype correlation. Methods: Trios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported SZT2 mutations were systematically reviewed to analyze the genotype-phenotype correlations. Results: SZT2 variants were identified in six unrelated cases with heterogeneous epilepsy, including one de novo null variant and five pairs of biallelic variants. These variants had no or low frequencies in controls. All missense variants were predicted to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients with null variants exhibited DEE. The patients with biallelic null mutations presented severe DEE featured by frequent spasms/tonic seizures and diffuse cortical dysplasia/periventricular nodular heterotopia. The three patients with biallelic missense variants presented mild partial epilepsy with favorable outcomes. Analysis of previously reported cases revealed that patients with biallelic null mutations presented significantly higher frequency of refractory seizures and earlier onset age of seizure than those with biallelic non-null mutations or with biallelic mutations containing one null variant. Significance: This study suggested that SZT2 variants were potentially associated with partial epilepsy with favorable outcomes without NDD, expanding the phenotypic spectrum of SZT2. The genotype-phenotype correlation helps in understanding the underlying mechanism of phenotypic variation.

DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation.

Background: The DLG3 gene encodes disks large membrane-associated guanylate kinase scaffold protein 3, which plays essential roles in the clustering of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses. Previously, DLG3 has been identified as the causative gene of X-linked intellectual developmental disorder-90 (XLID-90; OMIM# 300850). This study aims to explore the phenotypic spectrum of DLG3 and the genotype-phenotype correlation. Methods: Trios-based whole-exome sequencing was performed in patients with epilepsy of unknown causes. To analyze the genotype-phenotype correlations, previously reported DLG3 variants were systematically reviewed. Results: DLG3 variants were identified in seven unrelated cases with epilepsy. These variants had no hemizygous frequencies in controls. All variants were predicted to be damaging by silico tools and alter the hydrogen bonds with surrounding residues and/or protein stability. Four cases mainly presented with generalized seizures, including generalized tonic-clonic and myoclonic seizures, and the other three cases exhibited secondary generalized tonic-clonic seizures and focal seizures. Multifocal discharges were recorded in all cases during electroencephalography monitoring, including the four cases with generalized discharges initially but multifocal discharges after drug treating. Protein-protein interaction network analysis revealed that DLG3 interacts with 52 genes with high confidence, in which the majority of disease-causing genes were associated with a wide spectrum of neurodevelopmental disorder (NDD) and epilepsy. Three patients with variants locating outside functional domains all achieved seizure-free, while the four patients with variants locating in functional domains presented poor control of seizures. Analysis of previously reported cases revealed that patients with non-null variants presented higher percentages of epilepsy than those with null variants, suggesting a genotype-phenotype correlation. Significance: This study suggested that DLG3 variants were associated with epilepsy with/without NDD, expanding the phenotypic spectrum of DLG3. The observed genotype-phenotype correlation potentially contributes to the understanding of the underlying mechanisms driving phenotypic variation.

[Impact of maternal genetic effect on genetic parameter estimation of production traits for Qinghai fine-wool sheep].

The maternal genetic effects on estimating genetic parameters for growth traits and wool traits of Qinghai fine-wool sheep were investigated.The genetic parameters for production traits of Qinghai fine-wool sheep were estimated by average information restricted maximum likelihood (AIREML) with different animal models, and the differences between different animal models were tested by likelihood ratio test. Fixed effects, direct genetic effects, and residual effects were included all models; and random effects were individual permanence environmental effects, maternal genetic effects, and maternal permanence environmental effects. The six models differ in the way of considering random effects: in model 1 individual permanence environmental effects, maternal genetic effects, and maternal permanence environmental effects were not contained; in model 2 maternal permanence environmental effects were included; in model 3 maternal genetic effects were included; in model 4 both maternal genetic effects and maternal permanence environmental effects were include; in model 5 both individual permanence environmental effects and maternal genetic effects were contained;in model 6 all random effects were contained. The direct heritabilities were 0.1896~0.3781, 0.2537~0.2890, 0.2244~0.3225, 0.2205~0.3983, 0.1218~0.1490, 0.0983~0.4802, and 0.1170~0.1311 for birth weight, weaning weight, yearling weight, hogget weight,greasy fleece weight, fiber diameter, and staple length,respectively. Compared with model 1, model 3 was-significant(P<0.01) for birth weight and weaning weight, other models were not significant (P>0.05)for Yearling weight, Hogget weight; and paralleled with model 6, both model 4 and model 5 were significant(P<0.01) for fiber diameter,model 4 was significant(P<0.05) for staple length, and other models were not significant(P>0.05) for greasy fleece weight by likelihood ratio test.The maternal effects were important determinants of estimated the genetic parameters for birth weight, weaning weigh, fiber diameter, and staple length, but were not significant for yearling weight, and hogget weight, and was slightly significant for greasy fleece weight.

Fatty acid wax from epoxidation and hydrolysis treatments of waste cooking oil: synthesis and properties.

To provide low-cost wax and a new methodology for utilizing waste cooking oil (WCO), fatty acid wax based on WCO was synthesized by using epoxidation and hydrolysis treatments, whose properties included melting point, color, hardness, combustion properties, aldehyde content, and microscopic morphology were tested and analyzed. The obtained WCO-based wax contained mixed fatty acids, including palmitic acid and 9,10-dihydroxystearic acid as main constituents, which could form a 3D stable crossing network constructed by large long-rod crystals. The WCO-based wax with high fatty acid content (96.41 wt%) has a high melting point (44-53 °C), light color (Lovibond color code Y = 11.9, R = 2.3), good hardness (needle penetration index = 2.66 mm), long candle burning time (293 min), and low aldehyde content (7.98 × 10-2 µg g-1), which could be a lower-cost alternative of commercial soybean wax (SW) for producing various wax products including candles, crayons, waxworks, etc.

[Analysis of Clinical Characteristics of JAK2 V617F and BCR-ABL Double-Mutant Myeloproliferative Neoplasms].

OBJECTIVE: To analyze the disease types, clinical manifestations, efficacy and outcome of JAK2 V617F and BCR-ABL double-mutant myeloproliferative neoplasms (MPN), and provide a reference for the diagnosis, treatment and prognosis of MPN. METHODS: The clinical characteristics, diagnosis, therapeutic efficacy and outcome of JAK2 V617F and BCR-ABL double-mutant MPN were analyzed comprehensitively by combining a clinical case diagnosed and treated in our hospital with literature cases from CNKI and PubMed databases. RESULTS: A total of 38 related literatures were retrieved from the two databases by searching "JAK2 V617F" and "BCR-ABL" as key words from 1990 to 2019, and 59 cases were involved. Among all the 60 cases, 41 were males (68.3%) with a median age of 61 (32-77) years old, while 19 were females (31.7%) with a median age of 58 (21-82) years old. The BCR-ABL fusion gene and JAK2 V617F mutation were found simultaneously in 21 cases (35%), 19 cases (31.7%) with JAK2 V617F mutation were found during the treatment of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Ph+CML was detectable in 20 cases (33.3%) during the treatment of JAK2 V617F mutation positive MPN. Polycythemia vera (PV) was the most common MPN coexisting with CML (30%), followed by essential thrombocythemia (ET) (26.7%) and primary myelofibrosis (PMF) (21.7%). In addition, there were 13 cases (21.7%) not classified in the literature. Among the 60 cases, 35 CML patients were clearly staged, including 31 in the chronic phase, 3 in the accelerated phase, and 1 in the blast crisis phase. As for the subtypes of BCR-ABL fusion gene, there were 30 cases with clear classification, including 28 cases of p210, 1 case of p190 and 1 case of p230. CONCLUSION: As cases of BCR-ABL and JAK2 V617F double-mutant MPN are reported, simultaneous detection of JAK2 V617F mutation and BCR-ABL fusion gene in MPN patients is necessary to avoid misdiagnosis and missed diagnosis.

All-trans retinoic acid enhances cytotoxicity of CIK cells against human lung adenocarcinoma by upregulating MICA and IL-2 secretion.

To determine the growth inhibition capability of all-trans retinoic acid (ATRA) with cytokine-induced killer cells (CIKs), we evaluated their effects, alone and in combination, on human lung carcinoma A549 cells. CIKs treated with ATRA significantly inhibited cell growth. Additionally, CIK with ATRA synergistically inhibited migration and invasiveness, colony formation of A549 and NCI-H520 cells. Furthermore, analysis of apoptosis markers Bcl-2, Bax, Survivin and cleaved Caspase-3 showed that Bcl-2 and Survivin mRNA levels significantly decreased, and that Bax mRNA significantly increased, in the CIK + ATRA-treated cells, with corresponding effects on their respective proteins. The involved mechanisms may be associated with upregulated expression of MHC class I-Related Chain (MICA) and interleukin (IL)-2. These results suggest that administration of combined CIK and ATRA is a potentially novel treatment for lung carcinoma.